GUEST COMMENTARIES
`
`Bendamustine
`A Viewpoint by Patrick Schöffski
`and Arnold Ganser
`Department of Haematology/Oncology,
`Hannover Medical School, Hannover, Germany
`Bendamustine (Ribomustin®) is not a ‘new’ an-
`ticancer drug; its clinical use dates back to 1969,
`when the first objective responses (OR) were ob-
`served in patients with myeloma.[1] In vitro data
`indicated only limited cross-resistance to common
`agents such as cyclophosphamide, cisplatin, mel-
`phalan and doxorubicin, and the compound in-
`duced more long-lasting double-strand breaks than
`other alkylators. In subsequent dose-finding stud-
`ies in patients with solid tumours using the inter-
`mittent day 1 and 8[2] and continuous 30-minute
`weekly intravenous infusion[3] regimens, the drug
`was found to be very well tolerated. Mouth dry-
`ness, lymphopenia, fatigue and nausea were the
`most common adverse effects. In contrast to other
`commonly used agents, leucopenia and thrombo-
`cytopenia were not dose-limiting, and alopecia was
`not observed. Bendamustine, however, induced re-
`versible lymphocytopenia, affecting all types of
`lymphocytes including B, T and natural killer cells.
`Mild cardiac toxicity was found in these and other
`studies[4] in up to 16% of patients repeatedly ex-
`posed to the alkylating agent.
`Bendamustine has shown promise as first- and
`second-line treatment of patients with breast cancer.
`Substituting bendamustine for cyclophosphamide
`in the CMF (cyclophosphamide/methotrexate/
`fluorouracil) protocol extended the median dura-
`tion of remission from 6 to 15 months in 61 che-
`motherapy-naive patients with metastatic disease.
`The bendamustine regimen (BMF) achieved a 52%
`OR, which compared well with CMF (46%). A
`randomised multicentre phase III trial comparing
`BMF with CMF as first-line treatment in 364 non-
`pretreated patients completed accrual in January
`2001 and will help define the role of the drug in
`this setting. An ongoing randomised phase II trial
`is comparing weekly schedules of single-agent
`bendamustine and epirubicin in hormone-refractory
`patients with breast cancer.
`
`Drugs 2001; 61 (5): 639-640
`0012-6667/01/0005-0639/$27.50/0
`
`© Adis International Limited. All rights reserved.
`
`A 3-drug combination of bendamustine with
`doxorubicin and vincristine was active in patients
`pretreated with CMF. 50% of 62 relapsed patients
`achieved an OR. Responses were seen in bone, soft
`tissue and visceral sites.[5] As a single agent, ben-
`damustine salvage treatment achieved a 27% OR
`in 36 pretreated patients with advanced breast can-
`cer, and the efficacy was found to be independent
`of previous anthracycline treatment, consistent
`with the lack of cross-resistance seen in vitro. The
`role of bendamustine in patients previously ex-
`posed to either paclitaxel or docetaxel is being in-
`vestigated in an ongoing phase II programme.
`Bendamustine is currently also being studied in
`combinations with mitoxantrone and trials have
`been designed to test bendamustine together with
`the monoclonal antibody trastuzumab in HER-2-
`positive patients.
`Based on the lack of cross-resistance and only
`partially overlapping toxicity patterns with com-
`monly used agents for the treatment of breast can-
`cer, further studies with bendamustine in this tu-
`mour type are clearly warranted. According to our
`phase I experience with the pharmacological pro-
`file of this alkylating agent, weekly combinations
`with taxanes or 2-drug regimens with oral fluoro-
`pyrimidines such as capecitabine should be consid-
`ered for further testing. h
`
`References
`1. Anger G, Hesse P, Baufeld H. Behandlung des multiplen
`Myeloms mit einem neuen Zytostatikum. DMW 1969; 48:
`2495-500
`2. Schöffski P, Hagedorn T, Grünwald V, et al. Repeated admin-
`istration of bendamustine short infusions: a phase I study in
`patients with advanced progressive solid tumours. J Cancer
`Res Clin Oncol 2000; 126 (1): 41-7
`3. Schöffski P, Seeland G, Engel H, et al. Weekly administration
`of bendamustine: a phase I study in patients with advanced
`progressive solid tumours. Ann Oncol 2000; 11 (6): 729-34
`4. Reck M, Haering B, Koschel G, et al. Chemotherapie des
`fortgeschrittenen nichtkleinzelligen und kleinzelligen Bron-
`chialkarzinoms mit Bendamustin − eine Phase II-Studie.
`Pnenumologie 1998; 52: 570-3
`5. Brockmann B, Geschke E, Schmidt UM, et al. Therapie-
`ergebnisse und toxische Nebenwirkungen der Kombination
`Cytostasan, Adriamycin und Vincristine als ‘second-line’
`Therapie beim metastasierten Mammakarzinom. Geburt-
`shilfe Frauenheilkd 1991; 51 (5): 383-6
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`AGILA ET AL - EXHIBIT 1011